Abstract
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Objectives The αvβ6 integrin has recently been validated as a prognostic biomarker for non-small cell lung cancer (NSCLC). To utilize the αvβ6 integrin as a biomarker for molecular profiling of NSCLC, a peptide sequence with high binding affinity to the αvβ6 integrin was selected by phage display. Goal of this study was to develop novel positron emission tomography (PET) probes for noninvasive imaging assessment of NSCLC.
Methods The monomer and dimer forms of the peptide, H2009.1, were synthesized by standard solid-phase peptide chemistry and then conjugated to a bifunctional chelator scaffold featuring one or two maleimidyl functional groups and a cross-bridged tetraazamacrocylic core (CB-TE2A-MAL or CB-TE2A-(MAL)2) for 64Cu labeling. Three peptide conjugates (CB-TE2A-MAL-monomer, CB-TE2A-MAL-dimer, and CB-TE2A-(MAL-monomer)2 were synthesized and efficiently labeled with 64Cu under a mild condition within 30 min. The in vivo imaging evaluation was performed using two mouse models bearing H2009 (αvβ6+) and H460 (αvβ6-) tumors, respectively (n = 3 per group), on a Siemens Inveon PET-CT System.
Results On PET-CT images, the H2009 tumors were visualized by all three 64Cu-labeled conjugates at 1 h post-injection. The PET quantification revealed that the two bivalent conjugates had significantly higher H2009 tumor uptake than the monovalent one, while their uptake values in H460 tumors were low at the same level. This three-fold signal amplification in H2009 tumor indicates the role of the multivalent effect.
Conclusions We have developed a practical approach to prepare novel multivalent PET probes for molecular profiling of NSCLC via specific imaging of the αvβ6.integrin.
Research Support This work was partially supported by a USAMRMC grant (W81XWH-08-1-0305) and two NIH grants (U24 CA126608 and P01 DK058398)